Atrial thrombus caused by atrial fibrillation and thrombi formed by the disruption of atheroma (atherosclerotic vessels) in the aorta or carotid artery may cause ischemic cerebrovascular diseases such as cerebral embolism, cerebral infarction, transient ischemic attack, etc., and ischemic heart diseases such as angina pectoris, myocardial infarction, atrial thrombus caused by atrial fibrillation, cardiac insufficiency, etc. While blood circulation must have good fluidity to deliver oxygen and nutrients to body tissues and remove waste (from the circulatory system), it is required to be coagulative to stop bleeding for the prevention of blood loss due to injury. When the balance between such opposed functions of fluidity and coagulation is lost and shifts to coagulation, an intravascular thrombus is formed, which is thought to cause ischemic cerebrovascular disorders and heart diseases.
The fibrinolytic system plays important roles in thrombolysis, tissue destruction and repair, cell migration, etc. The fibrinolytic system is activated when plasminogen activator (hereinafter referred to as “PA”) converts plasminogen to plasmin, whereas plasminogen activator inhibitor-1 (PAI-1) inhibits PA.
Tissue plasminogen activator (hereinafter referred to as “t-PA”) converts plasminogen, i.e., the precursor of plasmin, to plasmin. Plasmin converts fibrin to a fibrin degradation product by breaking it down. PAI-1 is a serine protease inhibitor that specifically inhibits t-PA and urokinase plasminogen activator (hereinafter referred to as “u-PA”), suppresses plasmin generation, and as a result inhibits fibrin degradation.
Based on tertiary structural differences, PAI-1 is present in an active form that shows PA inhibitory activity and in a latent form that shows no PA inhibitory activity. In plasma, PAI-1 is known to be typically present in a concentration of 20 ng/mL, and produced in hepatocytes, megakaryocytes and lipocytes in addition to the vascular endothelial cells, which are the primary PAI-1 producing cells.
PAI-1 is an acute phase protein, and is thought to be one of the factors that cause ischemic organ dysfunctions in sepsis and disseminated intravascular coagulation syndrome (DIC) through accelerated production due to various cytokines and growth factors. Further, genetic polymorphism due to single base substitutions in the PAI-1 gene promoter is known, and it has been revealed that plasma PAI-1 concentration increases as a result of such genetic polymorphism.
Furthermore, in diabetes mellitus, accelerating arteriosclerosis and microvascular complications are presumed to be factors in ischemic heart disease, diabetic retinopathy and renal damage, i.e., all are critical complications of diabetes mellitus. For example, in diabetic nephropathy, increased extracellular matrix in the glomerulus and fibrous stroma are observed characteristics, and PAI-1 expression is increased in the glomerulus and renal tubules. In proximal renal tubule incubation, increased PAI-1 production is evident under hyperglycemic conditions. Further, a correlation between PAI-1 expression in renal tissues and macrophage infiltration is confirmed in experiments using a model mouse with renal interstitial fibrosis (non-patent document 1).
Furthermore, PAI-1 concentrations in urine are documented as being high in nephrotic syndrome patients based on the measurement results of PAI-1 levels in urine collected over a 24-hour period from nephrotic syndrome patients (see non-patent document 2).
As a result of administrating an inactive PAI-1 mutant (non-patent document 3) or t-PA (non-patent document 4) as a PAI-1 antagonist to a Thy-1 nephritis model, it is reported that the alleviation of inflammation (cellular infiltration), TGF-β suppression, and a decrease in mesangial matrix are observed, whereby Thy-1 nephritis is alleviated.
Reduced fibrinolytic activity due to an increased PAI-1 concentration in plasma is associated with ischemic heart diseases such as angina pectoris, myocardial infarction, cardiac insufficiency; deep-vein thrombosis and pulmonary embolism originated therefrom; and diabetic angiopathy. In addition to reduced fibrinolytic activity, some other thrombogenic abnormalities including hypercoagulation and platelet hyper-aggregation are also seen in diabetic patients. They are caused by microthrombus formation, and play important roles in the progress of diabetic microangiopathy and diabetic macroangiopathy. As described above, PAI-1 is presumably involved in the various pathologic formations and the progress of thromboses, cancers, diabetes mellitus, arteriosclerosis, etc. For this reason, a compound that inhibits PAI-1 activity is useful as a preventive and treatment agent for diseases associated with reduced fibrinolytic activity such as thromboses, cancers, diabetic complications, arteriosclerosis, etc. (non-patent document 5). Tissue fibril formation occurs in many tissues and organs such as the lungs, heart, blood vessels, liver, kidneys, etc.; however, there is no drug available to treat them radically. In reality, adrenocorticotropic hormones such as predonisolone, corticosteroid, etc., and cytotoxic drugs such as cyclophosphamide (alkylating agent) and azathioprine (antimetabolites, immunosuppressants) have been used as palliative therapy based on experience.
Non-patent document 1: Aya N. et al., J. Pathol., 166, 289-295, 1992
Non-patent document 2: Yoshida Y. et al., Nephron, 88, 24-29, 2001
Non-patent document 3: W. A. Border et al., J. Clin. Invest., 112, 379, 2003
Non-patent document 4: W. A. Border et al., Kidney Int, 59, 246, 2001
Non-patent document 5: Egelund R. et al., J. Biol. Chem., 276, 13077-13086, 2001